Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses

• Published in: Science advances Vol. 8; no. 8; p. eabi6110
• Main Authors: Nguyen, Long Chi, Yang, Dongbo, Nicolaescu, Vlad, Best, Thomas J, Gula, Haley, Saxena, Divyasha, Gabbard, Jon D, Chen, Shao-Nong, Ohtsuki, Takashi, Friesen, John Brent, Drayman, Nir, Mohamed, Adil, Dann, Christopher, Silva, Diane, Robinson-Mailman, Lydia, Valdespino, Andrea, Stock, Letícia, Suárez, Eva, Jones, Krysten A, Azizi, Saara-Anne, Demarco, Jennifer K, Severson, William E, Anderson, Charles D, Millis, James Michael, Dickinson, Bryan C, Tay, Savaş, Oakes, Scott A, Pauli, Guido F, Palmer, Kenneth E, Meltzer, David O, Randall, Glenn, Rosner, Marsha Rich
• Format: Journal Article
• Language: English
• Published: United States 25.02.2022
• Subjects: A549 Cells; Animals; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cannabidiol - chemistry; Cannabidiol - metabolism; Cannabidiol - pharmacology; Chlorocebus aethiops; COVID-19 - drug therapy; COVID-19 - virology; Endoplasmic Reticulum Stress - drug effects; Endoribonucleases - genetics; Endoribonucleases - metabolism; Epithelial Cells - virology; Female; Gene Expression Regulation, Viral - drug effects; Host-Pathogen Interactions - drug effects; Host-Pathogen Interactions - physiology; Humans; Immunity, Innate - drug effects; Interferons - metabolism; Mice; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; SARS-CoV-2 - drug effects; SARS-CoV-2 - physiology; Vero Cells; Virus Internalization - drug effects; Virus Replication - drug effects
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abi6110

The spread of SARS-CoV-2 and ongoing COVID-19 pandemic underscores the need for new treatments. Here we report that cannabidiol (CBD) inhibits infection of SARS-CoV-2 in cells and mice. CBD and its metabolite 7-OH-CBD, but not THC or other congeneric cannabinoids tested, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after viral entry, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD inhibits SARS-CoV-2 replication in part by up-regulating the host IRE1α RNase endoplasmic reticulum (ER) stress response and interferon signaling pathways. In matched groups of human patients from the National COVID Cohort Collaborative, CBD (100 mg/ml oral solution per medical records) had a significant negative association with positive SARS-CoV-2 tests. This study highlights CBD as a potential preventative agent for early-stage SARS-CoV-2 infection and merits future clinical trials. We caution against use of non-medical formulations including edibles, inhalants or topicals as a preventative or treatment therapy at the present time.